Benign prostatic hyperplasia (BPH) is an enigmatic reinitiation of prostate growth in aging men. The requirement of androgen by the male accessory sexual organs for normal growth and function is well established. While BPH requires the presence of a functioning testis, androgen levels and spermatogenic efficiency are generally declining at the time of onset, thus the reinitiation of growth, albeit abnormal, is paradoxical. Recently, transient neonatal hypothyroidism has been used to produce a near doubling of the testis and a 40-60% increase in ventral prostate size in the rat. This unusual and extended ventral prostate growth occurs in the presence of normal circulating androgen, growth hormone and prolactin levels. Recently, a body of evidence has accumulated indicating that non-androgenic factors, possibly produced by the testis or epididymis may act in concert with androgens to stimulate prostate growth. Our objectives in the proposed research focus on the non-androgenic effects of the testis and epididymis in the unusual prostate growth observed in these rate. To study the unusual growth in the treated rat's ventral prostate we propose to: 1. Characterize the pattern of ventral prostate growth in treated animals in order to evaluate where the excessive growth is occurring and if adult morphology is normal. Furthermore, a unique transplantation scheme will investigate if the observed over-growth is due to intrinsic or extrinsic changes. 2. Isolate and characterize specific protein/peptide factors which are mitogenic to prostatic cells in primary culture. Characterization to the peptide/nucleotide level will facilitate comparison with known mitogenic substances. 3. Localize the sites of expression and secretion of the candidate prostatic mitogens. This localization will include quantitative analyses in addition to message and cognate protein cellular localization. 4. Analysis of the effects of candidate mitogens on the expression of growth and/or programmed cell death associated genes, particularly of those associated with the AP-l transcription factors (fos and jun families. The potential synergistic effects of androgens and candidate mitogens will also be investigated. The proposed investigations using large scale protein separation, molecular cloning, in situ hybridization histochemistry, immunocytochemistry, protein and mRNA analyses, coupled with organ transplantation schemes, are expected to provide unique insight into the roles of androgens and nonandrogenic factors in facilitating and stimulating prostatic growth.